Loading...
Please wait, while we are loading the content...
Similar Documents
A QM/MM Evaluation of the Missing Step in the Reduction Mechanism of HMG-CoA by Human HMG-CoA Reductase
| Content Provider | MDPI |
|---|---|
| Author | Paula, Mihaljević-Jurič Sousa, Sérgio |
| Copyright Year | 2021 |
| Description | Statins are important drugs in the regulation of cholesterol levels in the human body that have as a primary target the enzyme β-hydroxy-β-methylglutaryl-CoA reductase (HMGR). This enzyme plays a crucial role in the mevalonate pathway, catalyzing the four-electron reduction of HMG-CoA to mevalonate. A second reduction step of this reaction mechanism has been the subject of much speculation in the literature, with different conflicting theories persisting to the present day. In this study, the different mechanistic hypotheses were evaluated with atomic-level detail through a combination of molecular dynamics simulations (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. The obtained Gibbs free activation and Gibbs free reaction energy (15 kcal $mol^{−1}$ and −40 kcal $mol^{−1}$) show that this hydride step takes place with the involvement of a cationic His405 and Lys639, and a neutral Glu98, while Asp715 remains in an anionic state. The results provide an atomic-level portrait of this step, clearly demonstrating the nature and protonation state of the amino acid residues involved, the energetics associated, and the structure and charge of the key participating atoms in the several intermediate states, finally elucidating this missing step. |
| Starting Page | 1085 |
| e-ISSN | 22279717 |
| DOI | 10.3390/pr9071085 |
| Journal | Processes |
| Issue Number | 7 |
| Volume Number | 9 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-06-23 |
| Access Restriction | Open |
| Subject Keyword | Processes Biophysics Atomic, Molecular and Chemical Physics Hmg-coa Hmg-coa Reductase Human Hmgr Reduction Mechanism Quantum Chemistry Qm/mm Oniom (own N-layer Integrated Molecular Orbital Molecular Mechanics) Dft (density Functional Theory) B3lyp |
| Content Type | Text |
| Resource Type | Article |
